title: Syntaxin 11 binds Vti1b and regulates late endosome to lysosome fusion in macrophages.
abstract: Syntaxin 11 (Stx11) is a SNARE protein enriched in cells of the immune system. Loss or mutation of Stx11 results in familial hemophagocytic lymphohistiocytosis type-4 (FHL-4), an autosomal recessive disorder of immune dysregulation characterized by high levels of inflammatory cytokines along with defects in T-cell and natural killer cell function. We show here Stx11 is located on endosomal membranes including late endosomes and lysosomes in macrophages. While Stx11 did not form a typical trans-SNARE complex, it did bind to the Q-SNARE Vti1b and was able to regulate the availability of Vti1b to form the Q-SNARE complexes Stx6/Stx7/Vtib and Stx7/Stx8/Vti1b. The mutant form of Stx11 sequestered Vti1b from forming the Q-SNARE complex that mediates late endosome to lysosome fusion. Depletion of Stx11 in activated macrophages leads to an accumulation of enlarged late endocytic compartments, increased trafficking to the cell surface and inhibition of late endosome to lysosome fusion. These phenotypes are rescued by the expression of an siRNA-resistant Stx11 construct in Stx11-depleted cells. Our results suggest that by regulating the availability of Vti1b, Stx11 regulates trafficking steps between late endosomes, lysosomes and the cell surface in macrophages.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Carolin
authors.initials: C
authors.lastname: Offenhäuser
authors.forename: Nazi
authors.initials: N
authors.lastname: Lei
authors.forename: Sandrine
authors.initials: S
authors.lastname: Roy
authors.forename: Brett M
authors.initials: BM
authors.lastname: Collins
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
authors.forename: Rachael Z
authors.initials: RZ
authors.lastname: Murray
mesh_terms: D000818:Animals; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D052118:Lysosomal-Associated Membrane Protein 1 / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D050766:Qb-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050600:SNARE Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D052118:Lysosomal-Associated Membrane Protein 1; D050765:Qa-SNARE Proteins; D050766:Qb-SNARE Proteins; D011993:Recombinant Fusion Proteins; D050600:SNARE Proteins; C491416:VTI1B protein, human